Although the etiologies of some secondary cataracts are becoming better understood and certain animal models show promise for elucidating the relationships between lens crystalline and hereditary cataract, little is known about the causes of congenital cataracts in humans. To date, the classification of different congenital cataracts has been cumbersome and imperfect. A better understanding of cataractogenesis will come through an understanding of the molecular components of the lens of the eye and the ways in which lesions of these components are manifested, structurally and functionally, as opacity of the lens. Animal studies have suggested that alterations in lens crystallins can cause hereditary cataracts, making them reasonable candidate genes for causing hereditary cataracts in humans. In addition, it is apparent that hereditary lesions that mimic or contribute additively to environmental stress known to cause cataracts might be candidate genes for causing hereditary cataracts. The work in this project is designed to specifically concentrate on congenital and complex hereditary cataracts and to take full advantage of molecular technology developed for linkage analysis. Studies performed on informative families will include collecting blood specimens from available family members and, when possible, analyzing lens material from patients who undergo cataract surgery. Lens crystallins comprise over 90% of the soluble protein of the lens and are heavily modified in most cataracts. The effects that specific modifications of beta and gamma-crystallin structure produce on crystallin functions, such as stability and formation of macromolecular aggregates, are being studied using SF9 cells transformed with bacculovirus vector containing coding sequences or normal and modified beta A3/A1- and B2-crystallin genes. Regions of the beta-crystallin molecule of special interest include the amino and carboxy terminal arms, the connecting peptide and the Greek key motifs of the core domains. In addition, the interactions of acidic and basic beta-crystallins are being studied.